12-122232361-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022916.6(VPS33A):c.1676C>T(p.Ala559Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS33A NM_022916.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.88

Genes affected

VPS33A (HGNC:18179): (VPS33A core subunit of CORVET and HOPS complexes) This gene encodes a tethering protein and a core subunit of the homotypic fusion and protein sorting (HOPS) complex. The HOPS complex and a second endosomal tethering complex called the class C core vacuole/endosome tethering (CORVET) complex, perform diverse functions in endocytosis including membrane tethering, RabGTPase interaction, activation and proofreading of synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) assembly to drive membrane fusion, and endosome-to-cytoskeleton attachment. The HOPS complex controls endosome maturation as well as endosome traffic to the lysosome. This complex is essential for vacuolar fusion and is required for adaptor protein complex 3-dependent transport from the golgi to the vacuole. The encoded protein belongs to the Sec1/Munc18 (SM) family of SNARE-mediated membrane fusion regulators. Naturally occurring mutations in this gene are associated with a novel mucopolysaccharidosis-like disease. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33A	NM_022916.6	c.1676C>T	p.Ala559Val	missense_variant	13/13	ENST00000267199.9
VPS33A	NM_001351018.2	c.1643C>T	p.Ala548Val	missense_variant	13/13
VPS33A	NM_001351019.2	c.1628C>T	p.Ala543Val	missense_variant	13/13
VPS33A	NM_001351020.2	c.1355C>T	p.Ala452Val	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33A	ENST00000267199.9	c.1676C>T	p.Ala559Val	missense_variant	13/13	1	NM_022916.6	P1
VPS33A	ENST00000643696.1	c.1799C>T	p.Ala600Val	missense_variant	14/14
VPS33A	ENST00000543633.5	c.*1637C>T		3_prime_UTR_variant, NMD_transcript_variant	14/14	5
VPS33A	ENST00000544349.6	c.*1655C>T		3_prime_UTR_variant, NMD_transcript_variant	14/14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 19, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 559 of the VPS33A protein (p.Ala559Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VPS33A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.015	D;.
Polyphen		1.0	D;.
Vest4		0.68
MutPred		0.85		Gain of catalytic residue at A559 (P = 0.2501);.;
MVP		0.49
MPC		1.1
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.76
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-122716908;